5alpha-halo-estran-10beta, 17beta-diol-3-one and intermediates and process therefor



United States Patent T 3,053,839 Sa-HALO-ESTRAN-IOB,17B-DIOL-3-ONE AND IN- TERMEDIATES AND PROCESS THEREFOR Jose Iriarte, Carl Djerassi, and Fred Allan Kincl, all of Mexico City, Mexico, assignors, by mesne assignments,

to Syntex Corporation, a corporation of Panama No Drawing. Filed Mar. 18, 1959, Ser. No. 800,085 Claims priority, application Mexico Mar. 19, 1958 12 Claims. (Cl. 260-23955) and In the above formulas R represents hydrogen or a lower alkyl of less than seven carbon atoms, or lower alkinyl or lower alkenyl. R represents hydrogen or when R is hydrogen, R represents hydrogen or a hydrocarbon carboxylic acyl group of up to 12 carbon atoms, substituted conventionally or unsubstituted, straight or branched chain aliphatic, cyclic or mixed cyclic-aliphatic. Typical are acetate, propionate, cyclopentylpropionate, benzoate etc. R represents lower alkyl or lower alkinyl. X represents fluorine, chlorine or bromine.

The novel compounds are prepared by a process illustrated as follows:

3,053,839 Patented Sept. 11, 1962 In the above equation X, R and R represent the same groups as heretofore. R represents hydrogen, lower alkyl or lower alkinyl.

In practicing the process above outlined, the nuclear double bond of the respective A -estren-17B-ol-3-one of Formula I was epoxidized by reaction with a peracid, which reaction has already been described in the case of the A -estren-17,8-ol-3-one Without substituent at C-17rc. The epoxide ring of the resulting 5,8,10,6-oxido compounds of Formula II was opened by reaction with a hydrogen halide to produce the halohydrins of Formula III (R =H). For the reaction with hydrogen fluoride we preferably employed boron trifluoride and thus produced the corresponding fluorohydrins; the chlorohydrins were obtained by reaction with pyridine hydrochloride "-33 Ra l? ,5

OT 1 0 Ir in mixture with a solvent inert to this reaction, such as ethanol; the bromohydrins were produced by reaction with concentrated aqueous hydrobromic acid in acetone solution.

The substituent at C- 17a of the starting compounds, and therefore also of the intermediate oxido-compound and of the halohydrins obtained thereof, may be a lower alkyl or alkinyl group, such as methyl, ethyl propyl, butyl, ethinyl, propinyl or butinyl. For preparing the halo hydrins having at C-17a an alkenyl substituent, such as vinyl, propenyl or butenyl, we hydrogenated partially the triple bond of the corresponding l7a-alkinyl-halohydrins.

Furthermore, the secondary hydroxyl group at 0-1713 of the halohydrins without the substituent at C-17oz was esterified by reaction with the anhydride of a hydrocarbon carboxylic acid of up to 12 carbon atoms to produce the corresponding 17-esters (III; R=H, R =acyl). The anhydride may be derived from a saturated or unsaturated acid, of straight or branched chain, cyclic or mixed cyclicaliphatic, substituted or not With methoxy, halogen or other groups and the esters formed include such as. the acetate, propionate, butyrate, hernisuccinate, enanthate, caproate, benzoate, trirnet-hylacetate, cyclopentylpropiom ate, phenylpropionate, phenoxyacetate and li-chloropropionate.

' The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I A mixture of 400 mg. of A -estren-17,6-ol-3-one and 10 cc. of chloroform was treated with a 0.44 N solution of monoper-phthalic acid in ether, at the temperature of a mixture of Dry Ice and acetone for 2 hours and then for 18 hours at 10 C. After pouring into water, the product was extracted with ether, Washed with sodium bicarbonate solution and water, dried over soditun sulfate and evaporated to dryness. Crystallization of the residue from acetone-hexane yielded 5 8,10{3-oxido-estran- 17B-ol-3-one, Ml. 208-210 C., [05],; 43 (chloroform), A max. 3500 and 1713 cm.-

Example I] A solution of 250 mg. of the above compound in a mixture of 30 cc. of anhydrous benzene and 15 cc. of absolute ether was treated with 0.5 cc. of boron trifluoride etherate and the mixture was kept standing at room temperature for 3 hours. It was then poured into water, extracted with ether and the extract was washed with water to neutral, dried over anhydrous sodium sulfate and evaporated. The residue crystallized from acetonehexane to produce Sa-fiuoro-estrane-lOfi,17}3-diol-3-one, M.P. 215217 (2., [th, 4l (chloroform).

Example III A solution of 200 mg. of Sfi,IOfl-oxido-estran-175-01-3- oue and 200 mg. of pyridine hydrochloride in 20 cc. oi absolute ethanol was heated under reflux for 3 hours. It was then poured into water and extracted with ethyl acetate; the extract was washed with water to neutral, dried over anhydrous sodium sulfate and the solvent was evaporated. Crystallization of the residue from methanol-benzene afforded Su-chloro-estrane-1013,17B-diol-3- one with M.P. 187-189" 0., [a1 +21 (methanol).

Example IV To a mixture of 200 mg. of 55,10/3-oxid0-estran-17fiol-3-one and 10 cc. of acetone there was added 0.5 cc. of aqueous concentrated hydrobromic acid and the mixture was kept standing for 3 hours. It was then diluted with water and the precipitate formed was collected by filtration, washed with water, dried in vacuum and crystallized from acetone-hexane. There was thus obtained 5a-bromo-estrane-10 3,17p-diol-3-one.

Example V Following the same method as that described in Example I, 17a-ethinyl-A -estren-17fi-o1-3-one was converted into 17a-ethinyl-5fl,10/3-oxido-estran-l7fl-ol-3-one with M.P. 185187 C., [0:]D 75 (methanol); A max. 2346 m log E 2.13, 11 max. (KBr): 3500, 3280 and 1710 cm."'

By the aforementioned reaction with boron trifiuon'de, as described in Example II, there was then obtained 17aethinyl-5a-fluoro-estrane-10 3,17B-diol-3-one; M.P. 247- 249 C. (crystallized from methanol-benzene); [a1 --40" (methanol); max. 230-6 Til 1., log E 2.21; v max. (KBr) 3640, 3460 and 1710 cmr To a suspension of 20 mg. of a pre-reduced 2% palladium on calcium carbonate catalyst in 5 cc. of pyridine there was added 200 mg. of 17nc-6thil1Yl-5oL-flllOl'O-ESEI'ZIIIC- 3,17/3-diol-3-one and the mixture was hydrogenated until the absorption of hydrogen practically ceased, which occurred when the equivalent of 1 mol of hydrogen had been absorbed. The catalyst was removed by filtration, washing the filter with ethyl acetate, and the combined filtrate and washings was washed with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and the ethylacetate was evaporated to dryness. The residue was purified by recrystallization from acetone-hexane, thus furnishing l7a-vinyl-5a-fiuoroestrane-10p,17fldiol-3-one.

Example VI By following the methods described in the previous examples, there were prepared all of the other 17a-alkyl alkenyl, alkinyD-analogs of Sa-halo (bromo, chloro and fluoro)-estrane-10,6,17B-diol-3-one comprised in our invention including the methyl, ethyl, propyl, butyl, propinyl, butinyl, propenyl and butenyl compounds.

Example VII A mixture of 1 g. of 5u-fiuoro-estrane-10B,l7 3-diol-3- one, 10 cc. of pyridine and 1 cc. of acetic anhydride was kept overnight at around 0 C. and then poured into water. The mixture was heated on the steam bath for half an hour and extracted with ether. The extract was washed with dilute hydrochloric acid, 5% sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness. Several recrystallizations of the residue from acetone-hexane yielded 50cfluoro-zs'trane-IOBJ7,8-dio1-3-one 17-acetate.

4 Example VIII By the same method there was acetylated the 17,8- hydroxyl group of 5a-chloro-estrane-105,17B-diol-3-one and of 5a-bromo-estrane-l0fi,17/3-dio1-3-one to produce the corresponding 17-acetates of such compounds.

Example IX By substituting in the method of Examples VII and VIII for acetic anhydride, another anhydride of a hydrocarbon carboxylic acid having up to 12 carbon atoms, there were prepared the corresponding 17-esters of the Sa-haIO-estrane-10,8,175-diol-3-ones including the caproates, cyclopentylpropionates and benzoates.

We claim:

1. A process for the production of SwhalOgen-estran- 1013,1713-diol-3-one compounds comprising reacting a A -estren-l7fi-ol-3-one compound with a peracid to form the corresponding 55,10,8-oxido compound and opening the oxide ring of the last mentioned compound with a hydrogen halide.

2. A compound of the following formula:

OH il 0 O- V wherein R is lower alkinyl.

3 17oc-6thi1'ly1-5 3, 10 3-oxido-estran-17fi-ol-3-one. 4. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkinyl, X is selected from the group consisting of fluorine, bromine and chlorine, R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl of up to 12 carbon atoms when R is hydrogen and R is hydrogen when R is other than hydrogen.

6. The 17-hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 5a-fluoroestran-10,8,17fi-diol-3-one.

7. 5a-bromo-estran-10fi,17/3-diol-3-one.

8. The 17-hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 5a-bromo-estran-10fi,17,6-diol-3- one.

9. Sa-chloro-estran-IOB,17fi-diol-3-one.

10. The 17-hydrocarbon carboxylic acid esters of up to 12 carbon atoms of 5a-chloro-estran-10B,17/?diol-3- one.

11. 17a-ethinyl-Sa-fluoro-estrane-l018,17B-diol-3-one.

12. 17a viny1-5 a-fiuoro-estrane-10B,17/3-diol-3-one.

References Cited in the file of this patent UNITED STATES PATENTS 2,729,654 Colton Ian. 3, 1956 2,806,862 Pederson et a1 Sept. 17, 1957 2,838,503 Herr et al. June 10, 1958 OTHER REFERENCES Ruelas et al.: J. Org. Chem, vol. 23, pp. 1744-47 (November 1958).

Nussbaum et al.: I.A.C.S., vol. 80, pp. 2722-2725 (June 5, 1958). 

2. A COMPOUND OF THE FOLLOWING FORMUL:
 4. A COMPOUND OF THE FOLLOWING FORMULA: 